DESCRIPTION: G-Protein Coupled Receptors (GPCRs) represent both the largest class of signaling receptors in the human genome and the family most targeted by therapeutic drugs. Responding to ligands that vary from protons to bioamines to lipids to chemokines, their attractiveness for drug discovery reflects the importance of the signals they transduce and, as has become apparent with the determination of their structures, the intrinsic ligand- ability of their binding sites. Despite intense interest, most GPCRs remain sparsely annotated by chemical matter. In this grant we will take a two-pronged approach to overcome these difficulties. In Specific Aim 1 we will develop and validate scalable assays in yeast and mammalian cells with which to screen a library of 5321 drugs and reagents. In Specific Aim 2 we will develop and validate scalable computational screens against modeled structures of the orphan GPCRs, leveraging the empirical hits. By the end of the project period we anticipate validating and executing physical screens against 30 orphan GPCRs and producing computationally optimized lead-like compounds for 20.